Two four-marker haplotypes on 7q36.1 region indicate that the potassium channel gene HERG1 (KCNH2, Kv11.1) is related to schizophrenia: a case control study

Abstract

Background: The pathobiology of schizophrenia is still unclear. Its current treatment mainly depends on antipsychotic drugs. A leading adverse effect of these medications is the acquired long QT syndrome, which results from the blockade of cardiac HERG1 channels (human ether-a-go-go-related gene potassium channels 1) by antipsychotic agents. The HERG1 channel is encoded by HERG1 (KCNH2, Kv11.1) gene and is most highly expressed in heart and brain. Genetic variations in HERG1 predispose to acquired long QT syndrome. We hypothesized that the blockade of HERG1 channels by antipsychotics might also be significant for their therapeutic mode of action, indicating a novel mechanism in the pathogenesis of schizophrenia.

Methods: We genotyped four single nucleotide polymorphisms (SNPs) in 7q36.1 region (two SNPs, rs1805123 and rs3800779, located on HERG1, and two SNPs, rs885684 and rs956642, at the 3'-downstream intergenic region) and then performed single SNP and haplotype association analyses in 84 patients with schizophrenia and 74 healthy controls after the exclusion of individuals having prolonged or shortened QT interval on electrocardiogram.

Results: Our analyses revealed that both genotype and allele frequencies of rs3800779 (c.307+585G>T) were significantly different between populations (P = 0.023 and P = 0.018, respectively). We also identified that two previously undescribed four-marker haplotypes which are nearly allelic opposite of each other and located in chr7:150225599-150302147bp position encompassing HERG1 were either overrepresented (A-A-A-T, the at-risk haplotype, P = 0.0007) or underrepresented (C-A-C-G, the protective haplotype, P = 0.005) in patients compared to controls.

Conclusions: Our results indicate that the potassium channel gene HERG1 is related to schizophrenia. Our findings may also implicate the whole family of HERG channels (HERG1, HERG2 and HERG3) in the pathogenesis of psychosis and its treatment.

Figure 1

Tetrameric organization and membrane topology of HERG1 channel. a: Orthogonal view from the extracellular side demonstrating the tetrameric organization of HERG1 channel. b: Longitudinal view through the channel, taken from the longitudinal section shown at the top, displaying the membrane topology of only two reciprocal components across the pore of the tetrameric HERG1 channel. The channel exhibits a tetrameric composition of one main alpha-subunit (HERG1 protein, shown as α and in plain gray) and one auxiliary beta-subunit (minK or MiRP1 protein, shown as β and in dotted gray). The alpha-subunit is composed of six transmembrane-spanning domains (labelled S1-S6), S1-S4 being the voltage-sensing domain and S5-S6 the pore-forming domain. The beta-subunit comprises one transmembrane-spanning domain. The NH₂ and COOH termini are also shown. α, alpha-subunit; β, beta-subunit; P, pore.

Figure 2

Location of the four SNPs analyzed in and around the HERG1 gene on 7q36.1 region. a: The 100 kb genomic region (shown as horizontal gray line) including the HERG1 gene (shown as gray rectangle) on 7q36.1. b: The organization of exons (shown as gray boxes) and introns (shown as horizontal gray lines) of the HERG1 gene. The four SNPs analyzed span ~76 kb on genomic DNA in chr7:150225599-150302147 bp position. Two SNPs (rs885684 and rs956642) are located at the 3'-downstream intergenic region of HERG1, and the other two SNPs (rs1805123 and rs3800779) are located respectively in exon 11 and intron 2 of the gene. Black circles (●) represent the SNP locations, and the rs numbers of SNPs are shown along the relevant arrows. SNP, single nucleotide polymorphism.

Figure 3

Linkage disequilibrium pattern of the SNPs along the 7q36.1 region encompassing the HERG1 gene. The graphic illustrates the one distinct haplotype block defined using the Haploview program. The linkage disequilibrium (D') between any two SNPs is shown in the cross cell. The darker the color indicates the higher linkage disequilibrium between any two SNPs. The linkage disequilibrium (r²) between any two SNPs is as follows: rs885684-rs956642: 0.191; rs885684-rs1805123: 0.277; rs885684-rs3800779: 0.122; rs956642-rs1805123: 0.081; rs956642-rs3800779: 0.072; rs1805123-rs3800779: 0.074. SNP, single nucleotide polymorphism.

Figure 4

Organization of genomic region and localization of haplotype blocks situated between positions 150150-150355 kb in 7q36.1. a: A 205 kb part situated between positions 150150-150355 kb of the 7q36.1 genomic region (gray horizontal line at the top), along with the genes ABP1, HERG1 (KCNH2), NOS3 and ATG9B located here (gray boxes), is shown. Relative position on 7q36.1 (marked by dotted lines) of the region investigated in the present study (~76 kb of length in chr7:150225599-150302147 bp position) is represented by the upper horizontal black line and that of Huffaker et al. (~65 kb of length in chr7:150280464-150345679 bp position; see text for the reference) by the lower horizontal black line. Black circles (●) on the upper horizontal black line indicate the locations of four SNPs analyzed in the present study, and the rs numbers of SNPs are presented along the relevant arrows. Small vertical lines (∣) on the lower horizontal black line indicate the locations of seven SNPs analyzed in all cohorts studied by Huffaker et al. rs3800779 is the single common SNP investigated in both studies and showed the higher significance among six significant SNPs found in the study of Huffaker et al. and the unique significance among four SNPs analyzed in the present study. Black horizontal rectangle at the bottom shows the position on 7q36.1 (marked by dotted lines) of the copy number variation (CNV, Variation 3711) of ~125 kb of length located in this part of the genome between positions 150169754-150294630 bp and partly inserted into HERG1 (~21.5 kb from its 3'-end). Three out of four SNPs (except rs3800779) that composes the schizophrenia-associated haplotypes A-A-A-T/C-A-C-G identified in the present study are located within this CNV. b: Haplotype blocks defined between positions 150150-150355 kb in 7q36.1 genomic region in the CEU population of the International HapMap Project http://hapmap.ncbi.nlm.nih.gov are shown. As marked by dotted lines, the schizophrenia-associated A-A-A-T/C-A-C-G haplotypes identified in the present study extend across a number of defined haplotype blocks. ABP1, amiloride binding protein 1 gene; NOS3, nitric oxide synthase 3 (endothelial cell) gene; ATG9B, nitric oxide synthase 3 antisense gene; SNP, single nucleotide polymorphism; CNV, copy number variation.